Role of Endothelium-Derived Nitric Oxide in the Pathogenesis of the Renal Hemodynamic Changes of Experimental Diabetes

To evaluate the role of nitric oxide (NO) in diabetic hyperfiltration, renal hemodynamic changes and changes in urinary excretion of NO2/NO3 in response to the NO inhibitor nitro-L-arginine methyl ester (L-NAME) and the NO-donating agent glyceryl trinitrate (GTN) were investigated in conscious streptozocin-induced diabetic (D) and age-matched control (C) rats. In all experiments, D rats demonstrated increased glomerular filtration rate (GFR), renal plasma flow (RPF), polyuria, and an increased urinary sodium excretion when compared with C rats. An intravenous bolus of low-dose L-NAME (1 mg/kg body wt) increased modestly systolic blood pressure (sBP) in C rats but had no effect on sBP in D rats. L-NAME induced a marked decrease in GFR and RPF in D rats with no change in filtration fraction (FF). In C rats, no change in GFR was observed, and RPF decreased, resulting in a rise in FF. A supramaximal dose of L-NAME (10 mg/kg body wt) increased sBP in C and D rats to a similar degree. With high-dose L-NAME, GFR decreased in D but not in C rats. There was a greater decrease in RPF in D rats when compared with C animals. An intravenous infusion of GTN induced a modest decrease in sBP in both C and D rats (P < 0.01). There were no changes in GFR and RPF in D rats, but in the C group, GTN increased RPF (P < 0.05) with a tendency for a rise in GFR (P = 0.09). Basal urinary NO2/NO3 excretion was increased in D rats in all experiments. A decrease in urinary NO2/NO3 levels was observed after low-dose L-NAME in D rats, with a similar trend after high-dose L-NAME. NO such changes were observed in C rats. GTN infusion had no effect on urinary NO2/NO3 excretion in D rats but increased urinary NO2/NO3 levels in C rats to levels that were not statistically different from those in D rats. These studies suggest that increased renal production and/or sensitivity to endothelium-derived relaxing factor/NO may play a role in the genesis of diabetic hyperfiltration.

[1]  M. Haneda,et al.  Antagonist for atrial natriuretic peptide receptors ameliorates glomerular hyperfiltration in diabetic rats. , 1993, Biochemical and biophysical research communications.

[2]  L. Raij,et al.  Abnormal renal hemodynamic response to reduced renal perfusion pressure in diabetic rats: role of NO. , 1993, The American journal of physiology.

[3]  H. Aynedjian,et al.  Role of EDRF (nitric oxide) in diabetic renal hyperfiltration. , 1993, Kidney international.

[4]  D. Brooks,et al.  Attenuated glomerular cGMP production and renal vasodilation in streptozotocin-induced diabetic rats. , 1993, The American journal of physiology.

[5]  G. Jerums,et al.  The Effects of Perindopril and Triple Therapy in a Normotensive Model of Diabetic Nephropathy , 1993, Diabetes.

[6]  A. Deng,et al.  Locally produced EDRF controls preglomerular resistance and ultrafiltration coefficient. , 1993, The American journal of physiology.

[7]  J. P. Tolins,et al.  Adaptation to increased dietary salt intake in the rat. Role of endogenous nitric oxide. , 1993, The Journal of clinical investigation.

[8]  M. Mcdaniel,et al.  Prevention of Diabetic Vascular Dysfunction by Guanidines: Inhibition of Nitric Oxide Synthase Versus Advanced Glycation End-Product Formation , 1993, Diabetes.

[9]  R. Cohen,et al.  DISFUNCTION OF VASCULAR ENDOTHELIUM IN DIABETES MELLITUS , 1993 .

[10]  L. Raij,et al.  Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. , 1992, The Journal of clinical investigation.

[11]  F. Salazar,et al.  Renal effects of prolonged synthesis inhibition of endothelium-derived nitric oxide. , 1992, Hypertension.

[12]  R. Johns,et al.  Nitric Oxide Alters Renal Function and Guanosine 3′,5′‐Cyclic Monophosphate , 1992, Hypertension.

[13]  N. Perico,et al.  Atrial Natriuretic Peptide and Prostacyclin Synergistically Mediate Hyperfiltration and Hyperperfusion of Diabetic Rats , 1992, Diabetes.

[14]  G. Jerums,et al.  Retardation by Aminoguanidine of Development of Albuminuria, Mesangial Expansion, and Tissue Fluorescence in Streptozocin-Induced Diabetic Rat , 1991, Diabetes.

[15]  R. Zatz,et al.  Effects of acute nitric oxide inhibition on rat glomerular microcirculation. , 1991, The American journal of physiology.

[16]  L. Ignarro,et al.  Comparison of the inhibitory potencies of N(G)-methyl-, N(G)-nitro- and N(G)-amino-L-arginine on EDRF function in the rat: evidence for continuous basal EDRF release. , 1991, The Journal of pharmacology and experimental therapeutics.

[17]  S. Gardiner,et al.  The effects of endothelin‐1 and NG‐nitro‐l‐arginine methyl ester on regional haemodynamics in conscious rats with streptozotocin‐induced diabetes mellitus , 1991, British journal of pharmacology.

[18]  C. Pollock,et al.  Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus. , 1991, The American journal of physiology.

[19]  B. Brenner,et al.  Nitric oxide: a potential mediator of amino acid-induced renal hyperemia and hyperfiltration. , 1991, Journal of the American Society of Nephrology : JASN.

[20]  L. Raij,et al.  Effects of Amino Acid Infusion on Renal Hemodynamics: Role of Endothelium‐Derived Relaxing Factor , 1991, Hypertension.

[21]  R. Cohen,et al.  Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. , 1991, The Journal of clinical investigation.

[22]  C. Baylis,et al.  Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney. , 1990, Journal of the American Society of Nephrology : JASN.

[23]  S. Gardiner,et al.  Regional and cardiac haemodynamic effects of NG‐nitro‐l‐arginine methyl ester in conscious, Long Evans rats , 1990, British journal of pharmacology.

[24]  G. Jerums,et al.  Glomerular Filtration Rate in Streptozocin-Induced Diabetic Rats: Role of Exchangeable Sodium, Vasoactive Hormones, and Insulin Therapy , 1990, Diabetes.

[25]  S. Moncada,et al.  Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses. , 1990, The American journal of physiology.

[26]  M. Steffes,et al.  Studies of renal autoregulation in pancreatectomized and streptozotocin diabetic rats. , 1990, Kidney international.

[27]  J. Vane,et al.  Endothelin‐1 and Endothelin‐3 Release EDRF from Isolated Perfused Arterial Vessels of the Rat and Rabbit , 1989, Journal of cardiovascular pharmacology.

[28]  D. Gardner,et al.  Urinary cGMP as biological marker of the renal activity of atrial natriuretic factor. , 1988, The American journal of physiology.

[29]  S. Moncada,et al.  Vascular endothelial cells synthesize nitric oxide from L-arginine , 1988, Nature.

[30]  H. Aynedjian,et al.  Sodium restriction corrects hyperfiltration of diabetes. , 1988, The American journal of physiology.

[31]  S. Harrap,et al.  Genetic co-segregation of renal haemodynamics and blood pressure in the spontaneously hypertensive rat. , 1988, Clinical science.

[32]  B. Brenner,et al.  Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration. , 1987, The Journal of clinical investigation.

[33]  A. Thomson,et al.  Endothelium-Dependent Relaxation in Aorta of BB Rat , 1987, Diabetes.

[34]  S. Moncada,et al.  Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor , 1987, Nature.

[35]  C. Mogensen,et al.  Predicting diabetic nephropathy in insulin-dependent patients. , 1984, The New England journal of medicine.

[36]  B. Bartholomew.  A rapid method for the assay of nitrate in urine using the nitrate reductase enzyme of Escherichia coli. , 1984, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[37]  S. Tannenbaum,et al.  Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. , 1982, Analytical biochemistry.

[38]  B. Brenner,et al.  Glomerular hemodynamics in experimental diabetes mellitus. , 1981, Kidney international.